Author: Fan, Xuemo ; Cui, Xiaojiang ; Liu, Qizhi ; Mozneb, Maedeh ; Arzt, Madelyn ; Yu, Changjun ; Huang, Faqing ; Zhang, Yi ; Cejas, Romina B ; Burridge, Paul W ; Gao, Bowen ; Giuliano, Armando E ; Pohlman, Stephany ; Sharma, Arun ; Jenkins, Amelia

The chemotherapeutic doxorubicin (DOX) detrimentally impacts the heart during cancer treatment. This necessitates development of non-cardiotoxic delivery systems that retain DOX anticancer efficacy. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), endothelial cells (hiPSC-ECs), cardiac fibroblasts (hiPSC-CFs), multi-lineage cardiac spheroids (hiPSC-CSs), patient-specific hiPSCs, and multiple human cancer cell lines to compare the anticancer efficacy and reduced cardiotoxicity of single protein encapsulated DOX (SPEDOX-6), to standard unformulated (UF) DOX. Cell viability assays and immunostaining in human cancer cells, hiPSC-ECs, and hiPSC-CFs revealed robust uptake of SPEDOX-6 and efficacy in killing these proliferative cell types. In contrast, hiPSC-CMs and hiPSC-CSs exhibited substantially lower cytotoxicity during SPEDOX-6 treatment compared with UF DOX. SPEDOX-6-treated hiPSC-CMs and hiPSC-CSs maintained their functionality, as indicated by sarcomere contractility assessment, calcium imaging, multielectrode arrays, and RNA sequencing. This study demonstrates the potential of SPEDOX-6 to alleviate cardiotoxic side effects associated with UF DOX, while maintaining its anticancer potency.

01 Nov 2020·Advanced Therapeutics

Single Protein Encapsulated Doxorubicin as an Efficacious Anticancer Therapeutic

Article

Author: Cook‐Wiens, Galen ; Huang, Faqing ; Chow, Warren A. ; Cui, Xiaojiang ; Yu, Changjun

AbstractSmall‐molecule chemotherapeutics are potent and effective against a variety of malignancies, but common and severe side effects restrict their clinical applications. Nanomedicine approaches represent a major focus for improving chemotherapy, but have met limited success. To overcome the limitations of chemotherapy drugs, a novel single protein encapsulation (SPE)‐based drug formulation and delivery platform is developed and its utility in improving doxorubicin (DOX) treatment is tested. Using this methodology, a series of SPEDOX complexes are generated by encapsulating various numbers of DOX molecules into a single human serum albumin (HSA) molecule. UV/fluorescence spectroscopy, membrane dialysis, and dynamic light scattering techniques show that SPEDOXs are stable and uniform as monomeric HSA and display unique properties distinct from those of DOX and DOX‐HSA mixture. Furthermore, detailed procedures to precisely monitor and control both DOX payload and binding strength to HSA are established. Breast cancer xenograft tumor studies reveal that SPEDOX‐6 treatment displays improved pharmacokinetic profiles, higher antitumor efficacy, and lower DOX accumulation in the heart tissue compared with unformulated DOX. This SPE technology, which does not involve nanoparticle assembly and modifications to either small‐molecule drugs or HSA, may open up a new avenue for developing new drug delivery systems to improve anticancer therapeutics.

01 Jan 2016·Cancer ScienceQ2 · MEDICINE

Radiolabeled liposome imaging determines an indication for liposomal anticancer agent in ovarian cancer mouse xenograft models

Q2 · MEDICINE

ArticleOA

Author: Funahashi, Yasuhiro ; Iwata, Masao ; Ito, Ken ; Fujii, Hirofumi ; Umeda, Izumi O. ; Asano, Makoto ; Hori, Yusaku ; Matsui, Junji ; Hamamichi, Shusei

Liposomal anticancer agents can effectively deliver drugs to tumor lesions, but their therapeutic effects are enhanced in only limited number of patients. Appropriate biomarkers to identify responder patients to these liposomal agents will improve their treatment efficacies. We carried out pharmacological and histopathological analyses of mouse xenograft models bearing human ovarian cancers (Caov‐3, SK‐OV‐3, KURAMOCHI, and TOV‐112D) to correlate the therapeutic effects of doxorubicin‐encapsulated liposome (Doxil®) and histological characteristics linked to the enhanced permeability and retention effect. We next generated 111In‐encapsulated liposomes to examine their capacities to determine indications for Doxil® treatment by single‐photon emission computed tomography (SPECT)/CT imaging. Antitumor activities of Doxil® were drastically enhanced in Caov‐3, moderately in SK‐OV‐3, and minimally in KURAMOCHI and TOV‐112D when compared to doxorubicin. Microvessel density and vascular perfusion were high in Caov‐3 and SK‐OV‐3, indicating a close relation with the enhanced antitumor effects. Next, 111In‐encapsulated liposomes were given i.v. to the animals. Their tumor accumulation and area under the curve values over 72 h were high in Caov‐3, relatively high in SK‐OV‐3, and low in two other tumors. Importantly, as both Doxil® effects and liposomal accumulation varied in the SK‐OV‐3 group, we individually obtained SPECT/CT images of SK‐OV‐3‐bearing mouse (n = 11) before Doxil® treatment. Clear correlation between liposomal tumor accumulation and effects of Doxil® was confirmed (R2 = 0.73). Taken together, our experiments definitely verified that enhanced therapeutic effects through liposomal formulations of anticancer agents depend on tumor accumulation of liposomes. Tumor accumulation of the radiolabeled liposomes evaluated by SPECT/CT imaging is applicable to appropriately determine indications for liposomal antitumor agents.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	US	The UC Irvine Medical Center	17 Nov 2022
Neoplasms	Phase 1	US	Sunstate Biosciences LLC	17 Nov 2022

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